1. Asthma & Exercise Physiology and Pathophysiology
Michele R. Shaw, RN, PhD

2. Asthma General Mechanisms
Inflammatory response
Involving T cells, mast cells, basophils, macrophages, T helper cells, and eosinophils
(Hamid et al., 2003; Macfarlane et al., 2000; Wegmann et al., 2005)
T lymphocytes (predominant cells involved in asthmatic airway mucosa)
(Hamid et al., 2003)
*Just for everyone’s review, remember that basophils & eosinophils are granulocytes (more than 1 nucleus) usually involved in the inflammatory response. Granulocytes release contents such as proteases and they are also capable of expression of adhesion molecules on their cell surface when they are activated. Eosinophils are increased in allergic reactions (keeping in mind that asthma has been associated with allergies). Basophils can bind with antigens and release histamine. Macrophages start as monoctyes which are agranulocytes (have 1 nucleus) and they too play a role in chronic inflammation. In addition, T cells are lymphocytes- one of the types of WBC’s or Leukocytes. T-helper cells secrete cytokines (or proteins) that help with the many functions of the immune system.
*T-lymphocytes are believed to be the predominant cells involved in the asthmatic airway mucosa, where upon stimulation (such as an acute asthma attack triggered by an allergen), they manufacture large amounts of cytokines. These cytokines are further broken down, I will discuss this on the next slide.

3. T Lymphocytes Produce large amounts of cytokines CD4+ (T helper cells)
Assist in the inflammatory response by signaling other cells to the area of inflammation.
CD8+ (T cytotoxic cells)
Assist by actually attempting to kill the invader
(Hamid et al., 2003)
*CD4 T Helper cells secrete cytokines (which are signaling proteins) to recruit other cells involved in the inflammation process.
*CD8 Cytotoxic T-cells can release perforin molecules to directly kill host cell

4. CD4+ T Helper Cells Broken down into Th1, Th2, and Th3
TH3 cells are another subtype of CD4+ cells and are suggested to be regulatory T helper cells.
Th3 are involved in high level production of transforming growth factor ß (TGF)
TGF, by binding to it’s type 1 and type 2 receptor sites, is thought to exert many physiological effects including, both anti-inflammatory and profibrotic activities.
Role of TGF is debated as it can assist in the ANTI-inflammatory process and/or have a profibrotic effect.
(Barbato et al., 2003).
*T-helper 1 cells secrete cytokines that help cytotoxic T-cells, while TH2 cells secrete cytokines that help B-cells secrete antibodies including IgE.
*Transforming Growth factor is thought to be involved in the remodeling process of asthmatic airways with it’s profibrotic effect (increased fibrosis or thickening). In a study done by Barbato and colleagues, they were interested in measuring inflammatory cells, basement membrane thickness, and transforming growth factor & it’s type 1 and type 2 receptor expression in asthmatic children. Findings demonstrated that asthmatic children had significantly decreased expression of their TGF type 2 receptor sites, when compared to the non asthmatic control group in their study. They hypothesized that due to the lack of adequate receptor sites, the asthmatic children where not able to exert the usual anti-inflammatory activities produced by TGF. Interestingly, this study did not find a significant correlation between transforming growth factor cells (or it’s receptors) and basement membrane thickness, suggesting TGF does not contribute to profibrotic activity (thus airway remodeling) in school aged children with asthma. These findings suggest the impaired TGF receptor sites may lead to the inflammatory manifestations seen in school aged children with asthma.

5. Cellular Counts in Subepithelium (Barbato et al., 2003)
Children with Asthma Children with Atopy Control Children
Eosinophils 48 (13–376)* 81 (8–330)* 15 (0–72)
Neutrophils 87 (16–244) 98 (19–225) 90(38–268)
Mast cells 23 (0–132) 93 (0–213) 56 (0–157)
CD4 T-lymph’s 89 (42–535) 259 (97–357) 213 (11–316)
Macrophages 175 (56–344) 138 (68–225) 137 (11–244)
TGFß1+ cells 182 (66–354) 172 (78–372) 87 (9–470)
TGFß-RI+ cells 623 (291–1167) 550 (308–1381) 952 (196–1,092)
TGFß-RII+ cells 179 (47–332)* 543 (391–676) 479 (71–948)
*Values are expressed as cells/mm2
*p<0.05 as compared with control children
*This is table 2 from the Barbato’s and colleagues study titled: Airway inflammation in childhood asthma.
*Notice the decreased transforming growth factor receptor 2. This was a statistically significant decrease p <.05 when compared to the control group children without asthma. Notice that the TGF cells were not significantly different among the 3 groups. So even though the asthmatic children were found to have increased number of eosinophils and thickened basement membranes when compared to the non asthmatic children, these findings were not significantly correlated to increased amounts of TGF cells.

6. Airway Remodeling Basement Membrane Thickening (Barbato’s et al)
Microphotograph showing bronchial biopsies from a child with asthma
Control child
Slide A demonstrates an increased basement membrane thickness in the child with asthma, (this increase in thickness of the membrane is believed to be part of the airway remodeling or scarring process)
*These pictures are from the same study discussed in the previous few slides. Barbato and colleagues were able to demonstrate that airway remodeling was occurring in children with asthma. Therefore the remodeling was occurring early in the disease process. The authors hypothesize airway scarring to occur parallel with the start of chronic inflammation (rather than the historical belief that remodeling occurs after years of chronic inflammation).

7. Airway Remodeling Increased Eosinophils
Increased eosinophils in asthmatics also contribute to airway remodeling. These slides are again from the Barbato and colleagues study of school aged children with asthma. *Remember from our notes that eosinophils have an affinity for red dye. Slide A represents a bronchial biopsy from an asthmatic child and the red areas are indicative of increased numbers of eosinophils infiltrating the subepithelium. Slide B is a control child without asthma.
*Just to summarize thus far, we have covered that asthma is characterized by an inflammatory response initiating a cascade of cellular events and these events lead to or occur simultaneously with airway remodeling.

8. Asthma and Exercise Phys/Pathophysiology
Two Hypotheses:
Heat loss & the re-warming of the airways leading to vascular engorgement = bronchoconstriction (McFadden & Gilbert, 1994; Anderson & Daviskas, 2000).
Dehydration of airways = changes initiating epithelial and mast cell activation = inflammatory process (McFadden & Gilbert; Anderson & Daviskas)
*the Inflammatory process includes the release of mediators such as histamines, leukotrienes, and prostanoids from the airway cells (Exercise is the trigger). The entire process is thought to cause the typical bronchial smooth muscle contraction or constriction seen in Exercise induced bronchoconstriction or EI asthma.
*These are the 2 basic ideas of causation for exercise induced asthma or exercise induced bronchoconstriction

9. Exercise as a non-drug treatment?
Pastva et al. (2004) hypothesized that moderate aerobic exercise would attenuate the inflammatory activities usually seen within the asthmatic airway.
Utilized a mouse model of atopic asthma.
Compared sedentary mice to an exercised group.
*Exercised mice utilized a motorized treadmill so that intensity and duration could be manipulated. Exercise sessions were performed 3xweek for a total of 4 weeks. During the first week of training, duration and speed were progressively increased to eventually reach around 60 minutes per session including warm up and cool down.

10. Sedentary Vs. Exercised Airway in a Mouse Model of Atopic Asthma (Pastva et al., (2004)
These pictures are of airway lumens of the mice. Picture A is from a sedentary mouse and B is from an exercised mouse, both mice had been experimentally induced with an asthmatic state. Notice the difference in airway diameter between the exercised and sedentary mice. The graph represents the differences in inflammatory parameters including: 1) perivascular and peribronchial lymphoid accumulations (*remember that the lymphoid tissues contain lymphocytes- they were measuring leukocyte infiltration). 2) hypertrophy (increase in size)& hyperplasia (which is an increase in number of cells) of the mucosal epithelium; 3) goblet cell and mucin production and(Goblet cells are glandular simple columnar epithelial cells whose sole function is to secrete mucus & Mucins which are a family of large, heavily glycosylated proteins which are increased in asthmatics) 4) overall index of inflammation. Notice that the dark lines represent the exercised group which scored lower in all inflammatory parameters! This was my favorite study! Now if we could just reproduce this with some asthmatic school aged children- kidding

11. Aerobic Exercise as Treatment…
Pastva et al (2004) findings demonstrate decreased inflammatory processes, including:
Mucus production & epithelial cell hypertrophy (lung tissue)
Cellular infiltrate & total protein concentration (airway lumen)
Secretion of the proinflammatory mediators (KC (a chemokine), IL-4, & IL-5 into the airway lumen)
Expression of the adhesion molecule VCAM-1 (vascular cell adhesion molecule-1 = promotes the adhesion of lymphocytes, monocytes, eosinophils, and basophils) (intact lung tissue)
Production of OVA-specific IgE in serum.
Summary: Data suggest moderate aerobic exercise reduces airway inflammation. Moderate training may provide beneficial anti-inflammatory effects in asthmatic humans.
*Further research needs to be done to investigate the Utilization of moderate aerobic exercise as a non drug treatment in school aged children with asthma. By starting early, it may be possible to provide a protective effect against airway inflammation, thus lessening symptom severity and disease progression.

12. Asthma Summary Complex disease with multiple etiologies.
Environmental & Genetic components
Decreased physical activity among school aged children may be a risk factor for development of asthma.
In addition, decreased activity may lead to an increase in symptom severity.
Need for further research among school aged asthmatic children, particularly in the area of exercise as a non-drug treatment.

13. Asthma and Exercise Model:
Moderate Aerobic Exercise
(Moderate aerobic exercise = 60 minutes, 3 times per week) ↓
↓ Inflammatory Response ↓
↓Asthma Symptoms & Severity↓
(among school aged children)
*Proposed asthma and exercise model: It is my hypothesis that with the correct dose of moderate aerobic exercise, the inflammatory response could be decreased which in turn would lead to decreased symptom and severity of asthma in school aged children.

14. Asthma & Exercise Physiology and Pathophysiology
Michele R. Shaw, RN, PhD